The Endocannabinoid System

"일단 저는 권용현이라고 하고요. 고려대학교 의과대학을 졸업을 한 의사입니다. 전문의 과정을 수료하지 않았기 때문에 저는 일반의고요. 대신에 석사과정을 한서대에 있는 건강증진대학원에서 수료를 했습니다. 논문을 안 써서 학위 논문은 마치지 못했고요." — a Korea University Medical College graduate; a general practitioner, not a specialist, since he didn't complete a specialist residency; graduate coursework at Hanseo University's Graduate School of Health Promotion, without finishing a thesis or receiving the degree.

"2015년 정도부터 본격적으로 카나비노이드 의학에 관심을 가지고 이런저런 활동을 하게 되었고요. 그러다 보니까 남들보다는 조금 일찍 눈을 뜨게 된 것 같아요. 그러다 그런 과정을 거치면서 지금 이 자리에서 여러분들과 함께 하게 되었고요." — serious interest in cannabinoid medicine from around 2015, which is what brought him to teaching this course.

Independent confirmation, not new information: /research already documents Hanseo University's Graduate School of Health Promotion (건강증진대학원), the Natural Health Care department, and that the master's course was never completed, from his own résumés and a direct note. This clip is him saying the same thing himself, on camera, to a different audience.

"이번 강의는 지난번 계속 말씀을 드린 것처럼 교육, 학술 및 연구를 위한 것이고 불법적인 사용을 조장하기 위한 것이 아님을 미리 밝히도록 하겠습니다." — stated plainly before the science starts: this course is for education, scholarship and research, and is not intended to encourage illegal use.

This is the same boundary the course's own docstring holds throughout — no clinical guidance, no legal claims — now in his own words rather than only in this file's own framing note.

Almost every physiological system was found by studying the body. This one was found by studying a plant. In 1964 Raphael Mechoulam and Yechiel Gaoni isolated Δ9-tetrahydrocannabinol from hashish and finally knew what the active molecule was. The obvious next question took twenty-six years to answer: what does it bind to?

In 1990 that binding site was cloned — a receptor, abundant in the brain, now called CB1. Three years later a second, concentrated in immune tissue, called CB2. And this is the moment the logic reverses. A receptor is not built for a plant. If the human brain is dense with a receptor that cannabis happens to fit, the brain must be making something of its own to fit it.

It was. In 1992 Devane and colleagues, working in Mechoulam's lab, pulled an endogenous ligand out of pig brain and named it anandamide — 아난다마이드 — after the Sanskrit ānanda, bliss. In 1995 came a second and far more abundant one, 2-arachidonoylglycerol, 2-AG.

So the naming is an accident of history. We call them endocannabinoids — 내인성 카나비노이드, endogenous cannabinoids — because we met the plant first. Had the order been reversed, we would call the plant compounds phyto-anandamides, and nobody would think this system had anything to do with cannabis at all. It is worth holding that thought for the whole course: this is your physiology, not a drug's.

내인성 카나비노이드 — 몸이 스스로 만드는 카나비노이드.

The endocannabinoid system is not an organ or a circuit. It is a signalling layer distributed across nearly every tissue — brain, gut, immune cells, bone, skin, liver — and what it does, everywhere, is regulate. It keeps other systems inside their range. The word for that is homeostasis, 항상성, and it is the single most useful frame for everything that follows.

Di Marzo's much-quoted summary of its functions is that it helps you relax, eat, sleep, forget, and protect. That is a mnemonic, not a mechanism — but it captures why a regulatory layer touches appetite, pain, mood, memory and immunity all at once, and why claims that it does everything are simultaneously exaggerated and not entirely wrong.

Which is also the trap. A system that modulates almost everything is irresistible to marketing. Nearly every overreach in this field starts from a true statement about breadth and slides into a false one about efficacy.

The receptor biology is textbook and is marked established. Clinical usefulness is a separate question with a separate answer per condition, and most of it sits at emerging or lower. Where the honest answer is that we do not know, the course says so — that is what the tiers are for, and in a field this commercially noisy it is the most valuable thing I can give you.

References

1. Gaoni, Y. & Mechoulam, R. (1964). Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society, 86(8), 1646–1647.●The isolation of THC — where the whole story starts.
2. Matsuda, L. A. et al. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561–564.●CB1 cloned — the receptor that implied an endogenous ligand.
3. Devane, W. A. et al. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258(5090), 1946–1949.●Anandamide.
4. Di Marzo, V., Bifulco, M. & De Petrocellis, L. (2004). The endocannabinoid system and its therapeutic exploitation. Nature Reviews Drug Discovery, 3, 771–784.●The review behind the homeostatic framing used throughout this course.

CB1 is among the most abundant G-protein-coupled receptors in the brain, concentrated where you would expect given the effects: basal ganglia and cerebellum (movement), hippocampus (memory), cortex, hypothalamus (appetite), and the periaqueductal grey (pain modulation). It is strikingly sparse in the brainstem regions that drive respiration — which is the accepted explanation for why cannabinoid overdose does not stop breathing the way opioid overdose does.

CB2 sits mainly on immune cells and in the periphery — spleen, tonsils, microglia, bone. Broadly, CB1 is the neuromodulatory arm and CB2 the immune-inflammatory arm, though the tidy split is a teaching simplification rather than a boundary.

Most neurotransmitters are packaged in vesicles and waiting. Endocannabinoids are not: they are lipids, cut out of the cell membrane at the moment they are needed, released immediately, and then destroyed. There is no reservoir to deplete and no store to fill.

The consequence matters more than it sounds. A system with no stockpile cannot be topped up by consuming its products, and its tone is set by rates — how fast it is synthesised, how fast it is broken down — rather than by how much of it exists. Almost every plausible-sounding intervention in this field is really a claim about one of those rates.

Here is the structural oddity. Ordinary synaptic transmission goes forward: the presynaptic cell speaks, the postsynaptic cell listens. Endocannabinoid signalling is retrograde — the postsynaptic cell makes the endocannabinoid and sends it back across the synapse, where it binds CB1 on the presynaptic terminal and tells it to release less.

So the listener turns down the speaker. That is a feedback brake, built into the synapse, and it is why the word for this system's job is regulation rather than excitation or inhibition. It does not carry a message; it adjusts the volume of messages already being sent.

If one image survives this course, let it be this one: not an accelerator, a governor.

Two enzymes end the signal. FAAH (fatty acid amide hydrolase) degrades anandamide; MAGL (monoacylglycerol lipase) degrades 2-AG. Because tone is set by rates, these enzymes are as much a part of the system as the receptors, and they are where a great deal of drug development has aimed — the idea being to raise your own endocannabinoid levels rather than introduce a plant agonist.

That approach has a cautionary history attached, and the next lessons come back to it. A brake you tamper with is still a brake.

References

1. Munro, S., Thomas, K. L. & Abu-Shaar, M. (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature, 365, 61–65.●CB2.
2. Mechoulam, R. et al. (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical Pharmacology, 50(1), 83–90.●2-AG — the more abundant of the two principal endocannabinoids.
3. Lu, H.-C. & Mackie, K. (2016). An Introduction to the Endogenous Cannabinoid System. Biological Psychiatry, 79(7), 516–525.●The clearest short review of the parts list and retrograde signalling.

Lesson one told the discovery in three beats. His own slide draws it with more steps between them, and they are worth having in order: 1964, Δ9-THC isolated. 1988, the first pharmacological evidence of a specific cannabinoid binding site in rat brain tissue, via radioligand assay — two years before that receptor was actually cloned. 1990, CB1 cloned. 1992, anandamide isolated. 1993, CB2 cloned. 1995, 2-AG identified, and the word endocannabinoid itself enters use.

1996 closes the loop lesson two describes without dating it: FAAH — the enzyme that ends anandamide's signal — is cloned. By 1996 the system had a receptor, two accepted messengers, and a named off switch, in that order. Discovery followed the logic of the system, not the other way around.

"엔도라는 말이 생물학에서는 많이 사용되는데 엔돌핀을 생각하시면 됩니다. 생물의 몸 안에 있는 모르핀이 엔돌핀인 거죠. 비슷하게, 엔도카나비노이드는 사람 몸 안에 있는 카나비노이드다." His own teaching analogy for the word itself, from the lecture audio: endorphin is to morphine what endocannabinoid is to cannabinoid — the body's own version of a compound named after the plant that led researchers to it.

"THC도 1964년에 처음 분리가 됐거든요. 그러니까 어떻게 보면 불법이 되고 나서야 이 식물에 대해서 연구가 조금 더 본격적으로 일어나기 시작한 거죠. 그래서 사실상 법을 만들었던 사람들이나 그동안 법을 집행을 해온 사람들도 제대로 몰랐던 거예요." His own observation on why the discovery ran 'backwards', the theme lesson one is named for: cannabis was made illegal before the plant was well understood, and serious research into what it actually was followed criminalisation rather than preceding it — the lawmakers and enforcers, by his account, didn't know either.

CB1 and CB2 are the classical pair lesson two covers. His slide's full table adds three more groups. Ionotropic: TRPV1 through TRPV4, TRPA1, TRPM8 — heat- and pain-sensing ion channels that several endocannabinoids and phytocannabinoids act on directly, not through CB1/CB2 at all. Novel or 'orphan' G-protein-coupled receptors: GPR3, GPR6, GPR12, GPR18, GPR55, GPR92, GPR119 — still being characterised, several with signalling that doesn't resemble CB1/CB2's. Nuclear receptors: PPARα, PPARγ, PPARδ — which is how cannabinoids reach gene transcription and metabolism, not only fast synaptic signalling.

The table also names non-cannabinoid receptors that endocannabinoids or phytocannabinoids happen to bind anyway: 5-HT1A, 5-HT3, the glycine receptor, adenosine A2A and A3, alpha-2 adrenergic receptors, mu and delta opioid receptors. This is the honest reason isolating 'the' effect of a given cannabinoid is hard — several of them are promiscuous ligands acting on unrelated receptor families at once, and a claim that names only CB1 or CB2 is usually incomplete rather than wrong.

"요새는 CB3의 수용체도 발견이 돼서 연구가 되고 있고." His lecture audio (clip 35) names a third classical-family member the slide table didn't: CB3, described only as recently discovered and under active research — held at emerging tier here since nothing further about its distribution or function is stated on this clip.

Beyond anandamide and 2-AG, his slide names a peptide class — pepcans, hemopressin-related — and two closely related lipids, PEA (palmitoylethanolamide) and OEA (oleoylethanolamide), structurally similar to anandamide but acting mostly outside CB1/CB2. Further modulators named: N-arachidonoyl amino acids, pregnenolone (which acts as a brake on CB1 signalling specifically, a hormonal buffer rather than a receptor ligand), and lipoxin A4.

Synthesis: DAGLα and DAGLβ make 2-AG; NAPE-PLD makes anandamide; PTPN22 is also listed on the synthesis side. Degradation: MAGL is 2-AG's main route; FAAH1 and FAAH2 handle anandamide; ABHD6 and ABHD12 are secondary routes for 2-AG; NAAA and the COX-2/LOX oxidative pathways are listed as further degradation routes — and COX-2/LOX are also inflammation-signalling enzymes in their own right, which the next lesson's inflammation pathway leans on directly. Transport — how a lipid moves from where it's made to where it acts, and to its own degrading enzyme, without a vesicle to carry it — is the one part of this table his slide names without settling; the mechanism is still an open question, not a gap in this transcription.

Ananda — bliss, in Sanskrit — plus amide, its chemical class. Lesson one already gives the name. What his slide adds is that how much of it you have is not the same for everyone: FAAH activity, which sets how fast anandamide is cleared, varies by a gene variant whose frequency differs by population — his slide cites approximate carrier rates of 21% in European Americans, 14% in East Asians, and 45% in Nigerians. Lower FAAH activity means anandamide clears more slowly, which in the studies behind this figure associates with a higher pain threshold and higher self-reported happiness.

That is a population-level pharmacogenetic finding, not a prediction about any one person, and this course holds it at that tier deliberately — the honest reading is 'this varies by more than lifestyle', not 'your ethnicity determines your baseline mood'.

His lecture audio for this slide (clip 35) confirms the same two figures — 14% and 45% — in his own voice, and also includes a spoken aside drawing a broader conclusion from them about ethnicity and capacity for happiness, citing a ~2015 study's popular interpretation. On his own instruction (2026-09-21) that aside is deliberately not carried into this lesson: by his own account it was an impression from meeting people of varied backgrounds, not a conclusion he stands behind, and the paragraph above already states the boundary correctly — the gene-frequency finding, not what any interpretation stretches it into.

Lesson two's closing line was that FAAH and MAGL are 'where a great deal of drug development has aimed' — raising your own endocannabinoid levels rather than introducing a plant agonist. His slide's diagram names the two standard research tools for exactly that: JZL184, which blocks MAGL and raises 2-AG, and URB597, which blocks FAAH and raises anandamide. Both are research compounds, not medicines available to write a prescription for, and their place in this lesson is mechanistic, not aspirational.

His slide's brain diagram maps the direction of effect by receptor: through CB1, rising anandamide associates with lower depression, lower pain, lower anxiety — and lower memory, the same trade-off lesson three names as useful forgetting rather than pure deficit. Separately through CB1: higher feeding, higher sleep. Through CB1 and CB2 together: lower neuro-inflammation, the mechanism the next lesson gives a full pathway.

This is the wiring diagram underneath what lesson three already claimed in outline — appetite, pain, memory, mood. Nothing here changes that lesson's tiers; it gives the same claims a specific circuit rather than a general statement of 'the system modulates this'.

References

1. Gaoni, Y. & Mechoulam, R. (1964). Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society, 86(8), 1646–1647.●1964 — already the opening date in lesson one.
2. Devane, W. A., Dysarz, F. A. III, Melvin, L. S., Johnson, M. R. & Howlett, A. C. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology, 34(5), 605–613.1988 — the radioligand evidence for a cannabinoid binding site, ahead of CB1's cloning.
3. Matsuda, L. A. et al. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561–564.1990 — CB1 cloned, already cited in lesson one.
4. Devane, W. A. et al. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258(5090), 1946–1949.1992 — anandamide, already cited in lesson one.
5. Munro, S., Thomas, K. L. & Abu-Shaar, M. (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature, 365, 61–65.1993 — CB2 cloned, already cited in lesson two.
6. Mechoulam, R. et al. (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical Pharmacology, 50(1), 83–90.1995 — 2-AG, already cited in lesson two.
7. Cravatt, B. F. et al. (1996). Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature, 384(6604), 83–87.1996 — FAAH cloned, closing the timeline this lesson adds.

CB1 activation in the hypothalamus and limbic system increases food intake and food reward. This is the least controversial functional claim in the field, and the proof came from the failed reverse: rimonabant, a CB1 blocker, was approved in Europe in 2006 as a weight-loss drug and worked — patients lost weight. It was withdrawn in 2008 because blocking CB1 also produced serious depression and anxiety.

Read that as a physiology lesson rather than a commercial failure. It demonstrated, in humans, that endocannabinoid tone is not a spare knob. Turn it down system-wide and mood goes with it — which tells you the same signalling layer holds appetite and affect in the same hand.

The system is present at every level of pain processing: peripheral nerve terminals, dorsal horn, and the descending modulatory pathways of the midbrain. That endocannabinoids modulate nociception is established physiology.

Whether cannabinoid drugs usefully treat pain in patients is a separate question with a much more cautious answer, and lesson five takes it up properly. Holding those two claims apart is most of what separates a clinician from a brochure.

Hippocampal CB1 activation impairs the formation of new memories — reliably, in animals and people. It is easy to read that as pure deficit, and acutely it is. But a system that dampens encoding is also a system for extinction: letting a learned association fade when it is no longer useful. That is not a failure of memory, it is maintenance of it.

This is the mechanism behind serious research interest in fear extinction and post-traumatic stress. I flag it as emerging, deliberately — the mechanism is sound, the human treatment evidence is early.

Via CB2 on immune cells and microglia, the system modulates cytokine release and inflammatory signalling. Again the direction of effect is regulatory rather than simply suppressive, which is why 'anti-inflammatory' is a poor one-word summary — the same layer can restrain an overshoot or permit a needed response depending on context.

By now the appeal is obvious: one system touching appetite, pain, memory, mood and immunity looks like a master key. But a regulator that reaches everywhere is exactly the thing you cannot push in one place without moving others — rimonabant is that sentence written as a clinical trial.

So the honest reading of breadth is not 'this treats many conditions'. It is 'intervening here has many consequences'. Those are close in wording and opposite in what they ask of a prescriber.

References

1. Christensen, R. et al. (2007). Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. The Lancet, 370(9600), 1706–1713.●The meta-analysis that made the psychiatric risk undeniable.
2. Lu, H.-C. & Mackie, K. (2016). An Introduction to the Endogenous Cannabinoid System. Biological Psychiatry, 79(7), 516–525.●Functional distribution across pain, memory and appetite circuits.

His slide draws a body map, not just a list. CB1: concentrated in brain and central nervous system, but also present in peripheral nerves and other organs. CB2: mainly bone, skin, and tissue that interacts with the immune system. TRPV1: blood, bone, bone marrow, tongue, kidney, liver, stomach, and ovaries. TRPV2: concentrated in skin, muscle, kidney, stomach, and lungs. GPR18: mainly bone marrow, spleen, and lymph nodes. GPR55: bone and brain — especially the cerebellum — plus the duodenum and small intestine generally. GPR119: pancreas and the digestive tract.

The receptors the previous lesson named as a taxonomy get a geography here — CB1/CB2 are not the only ones with a mapped distribution, and several of the others sit in tissue neither receptor reaches (bone marrow, cerebellum, pancreas).

"뇌의 브레인 거트 액시스라고 하는데 뇌하고 소장이 연결이 되어 있거든요. 거기에서 상당히 중요한 역할을 하고 있고요." His lecture audio names why GPR55's brain-plus-small-intestine distribution matters specifically: it sits on the brain-gut axis, the direct communication line between the two, rather than just happening to occupy two unrelated sites.

His slide's HPA-axis diagram: prefrontal cortex, amygdala and hippocampus signal down through ACTH, the anterior pituitary, and the adrenal cortex, releasing cortisol in a loop that stress activates. Named effects of stress on this system specifically: AEA levels fall, FAAH expression rises, CB1 receptor levels fall. Named consequences: higher pain sensitivity, worse sleep quality, higher anxiety, and lower resilience in recovering from trauma.

Worth stating plainly rather than smoothing over: this is a system meant to buffer stress that is measurably degraded by sustained stress rather than reinforced by it — anandamide tone falls exactly when its regulatory job matters most. His slide's molecular detail adds one more asymmetry: CRH/CRH1 signalling and cortisol rise together with FAAH, while GR and CB1 fall — but 2-AG rises over the same stretch. The two principal endocannabinoids do not move in the same direction under chronic stress, which this lesson states rather than resolves.

"이 반응들은 피드백 관계이기 때문에 일방적이라기보다 통증에 민감할수록 스트레스를 잘 받게 되고, 스트레스를 받으면서 통증에 민감해지는 이런 식으로 상호 피드백 작용이 일어난 거죠." His own framing, from the lecture audio, of why this isn't a one-way cascade: pain sensitivity and stress reactivity feed each other, each making the other worse, rather than stress simply causing pain sensitivity as an endpoint.

Lesson three said the system is 'present at every level of pain processing' without drawing the circuit. His slide does: CB1 reduces pain perception and the biochemical pain response, and separately changes the emotional and conscious component of pain — the same mood/memory territory lesson three and this lesson's earlier section both touch. CB2 acts on peripheral immune cells and on microglia in the central nervous system, modulating the nociceptive response specifically in neuropathic or inflammatory pain.

The pathway itself: ascending pain signal travels periphery to thalamus to cortex/limbic system, and CB1R at the thalamus inhibits that ascending transmission while also shaping how the cortex and limbic system interpret it emotionally. A separate, descending route runs the other way — CB1R activates inhibitory signalling through the periaqueductal grey and the nucleus raphe magnus, which reaches back down to the periphery, where CB2R inhibits neuronal sensitisation and ascending transmission at the source.

CB2 activation reduces inflammation; acute and chronic inflammation both drive pain, which is why this lesson and the previous one sit next to each other on his slide. He names this pathway as a lead into non-communicable disease broadly — cancer, liver disease, cardiovascular disease, and what his lecture audio names directly as 성인병 (metabolic/lifestyle disease) — rather than a treatment claim for any one of them.

Two routes, per his diagram. Peripherally, cannabinoids act on macrophages and B-cells through TRPV1, CB2 and GPR55, lowering COX-2, iNOS and TNF-α. Centrally, CB2 in the brain acts partly through PPARγ, lowering AKT/ERK/NF-κB/iNOS signalling and lipid peroxidation. Both routes converge on the same two outcomes: fewer inflammatory cytokines, less inflammation overall — one more instance of a signalling layer reaching nearly every tissue, the frame lesson one opened with.

His slide's own name for it, typo included: CECD, Clinical EndoCannabinoid Defiency, proposed by Dr. Ethan Russo. The hypothesis: that chronic underperformance of the endocannabinoid system itself may contribute to a cluster of otherwise unrelated, treatment-resistant conditions — his slide names migraine, fibromyalgia and depression among them. The proposed mechanism runs through the same genetics as the anandamide lesson: FAAH and MAGL gene variants, where lower FAAH activity associates with a higher pain threshold and higher self-reported happiness, and variant frequency differs by population.

His slide's closing line, transcribed as far as it is legible on screen: phytocannabinoids such as CBD and THC are proposed to support a deficient system through FABP — fatty-acid-binding proteins, which ferry endocannabinoids toward the enzymes that degrade them — and through direct CB-receptor activity. The rest of that sentence runs off the visible slide and is not completed here.

"카나비노이드를 섭취를 하면 병이 치료가 되는데 이러한 개념이 아니고, 애초에 카나비노이드가 부족해서 병이 생기는 거야라고 이제 관점을 좀 바꿔버린 겁니다." His own framing of what makes CECD a distinct hypothesis rather than a restatement of 'cannabis treats disease': the claim runs the other way — that a deficiency in the system itself may be upstream of the disease, not that supplementing cannabinoids is a treatment for it. The distinction is his; this lesson's own tier and aside already held that line before this audio confirmed he draws it the same way.

CECD is a research hypothesis with a named proposer and a proposed mechanism, not a diagnosis anyone can be tested for and given today. This lesson names it because his slide does; it is not a claim that any named condition is caused by it, and it is not treatment guidance.

References

1. Crowe, M. S. et al. (2014). The endocannabinoid system modulates stress, emotionality, and inflammation. Brain, Behavior, and Immunity.●The endocannabinoid system's documented role in stress and inflammation, matching this lesson's HPA-axis and inflammation sections.
2. Russo, E. B. (2004). Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinology Letters.◗The CECD hypothesis itself, naming the same conditions his slide does.

THC binds CB1 as a partial agonist — it activates the receptor, but less completely than the body's own 2-AG would at full occupancy. Two things follow. It produces effects broadly like an endocannabinoid surge but blunter and far longer-lasting, because it is not cleared by FAAH or MAGL on the timescale your own messengers are. And its dose–response is not a straight line: more is not reliably more, and past a point the anxiolytic becomes anxiogenic.

The long half-life is the part most often missed. Your own system signals in seconds, locally, and then destroys the messenger. An inhaled plant agonist occupies the same receptors for hours, everywhere at once. Same receptor; entirely different pattern of use.

Cannabidiol is where careless teaching does the most damage. CBD has very low affinity for CB1 — it is not 'the calm one at the same receptor'. Its documented actions are elsewhere: it is a negative allosteric modulator at CB1 (it changes how other ligands act there rather than activating it), and it interacts with TRPV1, 5-HT1A, adenosine signalling, and FAAH activity among others.

So when someone tells you CBD works 'through the endocannabinoid system', ask which part. Sometimes the answer is real; often the phrase is doing the work that evidence should.

The term comes from a 1998 paper by Ben-Shabat, Mechoulam and colleagues, describing inactive lipids that enhanced 2-AG activity. It was later extended by Ethan Russo into a broader hypothesis: that whole-plant preparations, with their minor cannabinoids and terpenes, act differently from isolated THC.

The hypothesis is plausible and partly supported in preclinical work. It is also the single most commercially useful claim in the industry, which is precisely why it needs its tier stated out loud. Marked emerging: real research, genuinely open, routinely sold as though it were established.

A product label reporting a high THC percentage is telling you about concentration, not about clinical usefulness, and not about whether the effect you want will arrive. Pharmacologically these are separate axes — affinity, efficacy, dose, route, and the state of the system you are acting on. Conflating them is the most common error in consumer conversation about this plant, and it is worth being able to explain the difference in one sentence.

References

1. Ben-Shabat, S. et al. (1998). An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. European Journal of Pharmacology, 353(1), 23–31.●Where the term originates — narrower than its current usage.
2. Russo, E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology, 163(7), 1344–1364.◗The broad hypothesis, cited as hypothesis.
3. Laprairie, R. B. et al. (2015). Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. British Journal of Pharmacology, 172(20), 4790–4805.●Why CBD is not simply a CB1 agonist.

"이 사상체가 형성이 되면 이 안에서는 카나비노이드를 합성하는 화학적인 회로가 형성이 됩니다. [...] 왼쪽 위에 있는 것이 CBGA인데요. CBGA가 거의 모든 카나비노이드의 전구체 역할을 합니다. 그래서 이제 CBGA에서 CBG로 합성이 되기도 하고 혹은 THCA로 합성이 되기도 하고요. CBDA로 합성이 되기도 하고 CBCA로 합성이 되기도 합니다. 그러니까 어떤 카나비노이드로 어느 정도가 합성이 되는지는 종자에 따라서 차이가 있는 거죠."

Once the trichome (사상체) forms, a chemical circuit inside it starts synthesising cannabinoids from one shared precursor, CBGA — branching into CBG, THCA, CBDA or CBCA depending on which enzymes the seed's own genetics express. This confirms the existing framing exactly; nothing here changes.

"THCA는 델타9THC의 전구체가 돼서 이제 시간이 지나면서 델타9THC로 바뀌게 되고 CBDA는 시간이 지나면서 CBD로 바뀌게 됩니다. CBCA는 이제 CBC로 바뀌게 되고요. 보통 이제 뒤에 A가 붙으면 전구체 역할을 한다고 생각을 하시면 될 것 같습니다." His own shorthand for the whole decarboxylation story: a trailing 'A' means precursor.

"시간이 지나면 카나비노이드들이 생기면서 투명했던 사상체가 불투명하게 바뀝니다. 하얗게 속이 차오르게 되고요. 시간이 흐르면서 후기에 이르면 형성이 되었던 델타9THC가 CBN으로 바뀌기도 하고요. 혹은 델타8THC로 바뀌기도 합니다."

"호박색으로 바뀌게 되면 몸이 좀 이완이 되고 진정이 되는 효과가 좀 더 강하고, 그 이전 단계, 그러니까 사상체가 하얗게 차있는 단계에서는 [...] THC나 CBD 중간 단계의 [...] 그에 해당한 어떤 정신적인 작용이 더 크다라고 이제 여기서 보게 됩니다. 그래서 원하는 효과나 기대하는 효과에 따라서 수확 시기도 좀 달라지게 되고요."

This is new detail the slides alone didn't carry: as the trichome ages from clear to cloudy white to amber, its chemistry shifts — cloudy white tracks with more of the mentally-active THC/CBD stage, amber tracks with THC having degraded further toward the more sedating CBN. A grower's harvest timing is, on his account, a choice about which of those states the crop is picked in.

"생산 과정에서는 이 식물 자체가 자외선으로부터 보호를 하기 위해서 THC나 CBD를 생성을 한다라고 이제 연구가 되어 있고요. 그리고 또 다른 카나비노이드들 같은 경우는 벌레에 대한 독성 혹은 이제 살균 작용으로 인해서 식물이 스스로를 어떤 병충해로부터 스스로를 지키기 위해서 이러한 성분들을 만들어낸다고도 합니다." — matching the UV-protection, insecticidal and antimicrobial framing already drafted here.

One claim he explicitly hedges rather than states as established: "혹자에 따르면 이제 대마를 섭취한 벌레가 어디에서 그 섭취를 했는지 기억을 못하게 해서 다시 찾아오지 못하게 한다는 그런 이야기도 있더라고요" — 'some say' an insect that eats the plant forgets where it fed, so it doesn't return. Carried here at the same hedge he gives it, not upgraded to a claim of his own.

"이러한 작용들이 이제 사람에게 사용을 했을 때도 마찬가지로 적용이 되는 거죠. 예를 들면 이제 CBD나 THC를 피부에 도포를 했을 때 피부를 이제 재생을 하거나 외부 환경으로부터 보호를 해주는 작용을 한다든지." His own bridge from plant defence to topical use in people — skin regeneration and protection, offered as the same logic extended, not a separate claim.

THC is not a stable endpoint. Exposed to oxygen, heat and light over time, it oxidizes into cannabinol (CBN) — which is why older, poorly stored cannabis is reported as more sedating and less potent: CBN binds CB1 far more weakly than THC. THC can also isomerize into D8-THC, a milder, less common analogue.

Inside the body, the liver does its own version of this chemistry. THC is first hydroxylated into 11-OH-THC — itself active, and the main reason edibles feel different from smoking: oral THC passes through the liver before reaching circulation, so a meaningfully larger fraction becomes this stronger, slower, longer-lasting metabolite than when THC is inhaled. 11-OH-THC is then oxidized further into 11-nor-9-carboxy-THC (THC-COOH), which is not psychoactive but is fat-soluble and slow to clear — the metabolite standard urine drug screens actually detect, sometimes for weeks after last use in regular users.

The three-word sequence growers use — harvest, dry, cure — is where a plant's chemistry stops changing rapidly and starts to stabilise: drying removes water so the aromatic terpenes and cannabinoids formed during growth aren't lost to rot or evaporation, and curing, a slower controlled aging period, is reported to smooth harshness and shift the balance of what survives. The trichome-colour section above is his own account of the harvest-timing half of this; the drying/curing technique itself he still doesn't detail on this clip.

Citing a consumer survey (a site he names sounds, on the recording, like "Leafly" — the well-known cannabis review site — though the exact name is not fully clear on this transcript): "연기를 피우는 게 가장 흔하고 46%가 가장 흔하고, 그 다음이 이제 정제되어 있는 캡슐의 형태로 섭취하거나 혹은 브라운이나 쿠키나 초콜릿, 캔디, 요새는 젤리 같은 음식의 형태로 섭취를 하는 게 16%, 16.5% [...] 두 번째로 흔한 걸로 되어 있고, 이제 연기는 연기인데 이제 기화기를 사용을 하는 게 13% [...] CBD 오일 같은 틴크처를 사용을 하는 게 5.5%, 뭐 마시거나 혹은 이제 바르는 연고나 화장품으로 사용을 하는 게 각각 1.5%로 되어 있습니다." — smoking 46%, edibles ~16.5%, vaporizing 13%, tinctures 5.5%, drinks and topicals 1.5% each, by his account of that survey.

"한 연구에 따르면 의료용 대마 사용자들 중에서 86.6% [흡입을] 선호한다고 합니다." He notes he'll return to what 'medical cannabis' (의료용 대마) actually means as a term later in the course — flagged here rather than defined, since he explicitly defers it himself.

His slides catalogue the common methods rather than endorsing any: rolled into a joint (in paper) or a blunt (in a tobacco-leaf wrapper), smoked from a pipe, or drawn through a water pipe that cools and filters smoke through water before it's inhaled. Vaporizers heat plant material or concentrate below the point of combustion — some, app-connected, let a user log temperature and dose per session. THCA diamonds — crystallised, near-pure THCA — sit at the potent end of what a pipe or vaporizer can deliver.

Route matters pharmacologically, not just as a matter of preference. Inhaled THC reaches the brain in minutes and clears relatively quickly; swallowed THC is metabolised by the liver first into 11-OH-THC before it reaches circulation — the stronger, slower metabolite the previous lesson covers — which is the chemical reason edibles are reported to feel different, take longer to arrive, and last longer than smoking the same plant. See e13 for the fuller pharmacokinetic arc, now written from this same clip.

"만성적으로 사용을 할 때는 기관지염이나 기침이나 객담 같은 호흡기 증상과 연관이 되어있다고 연구가 되어있고요. 다만 대마만 사용을 했을 때는 만성폐쇄성 폐질환이나 폐암은 발생하지 않는 걸로 되어있습니다. 담배를 같이 사용하는 인구가 많기 때문에 담배를 같이 사용하게 되면 아무래도 그런 리스크도 많이 발생할 수가 있겠죠." — chronic smoking is linked to bronchitis, cough and sputum, but cannabis alone (isolating out co-occurring tobacco use) is not linked to COPD or lung cancer in the research he cites. He names this distinction himself rather than leaving smoking risk as one undifferentiated claim.

The oldest methods use only mechanical force or heat. Charas and hashish are made by hand-rubbing or sieving the plant's resin glands off the flower and compressing what collects. Dry sieve or kief is the same trichome material, mechanically separated through a screen rather than by hand. Rosin applies heat and pressure directly to flower or hash, squeezing the resin out with nothing added — no chemical residue to remove afterward, which is the main appeal of this whole category.

"19세기의 유럽에 해시시 클럽이라고 있었다고 하더라고요. 당시에 이제 유명한 문인들이라든지 예술인들이 모여있던 클럽이었는데 그들이 이제 이 해시시를 사용을 하면서 받은 영감을 가지고 작품 활동을 했다고 합니다." His own aside on hashish's history — the 19th-century Paris Club des Hashischins, whose members (he names Baudelaire as the best-known) wrote about the experience — offered as cultural context for the oldest extraction method, not a claim about effects.

Solvent extraction dissolves cannabinoids and terpenes out of the plant material, then removes the solvent, leaving a concentrate behind. Ethanol is polar and pulls chlorophyll and plant pigment along with the cannabinoids, needing more purification afterward; butane and hexane are non-polar and pull a cleaner cannabinoid/terpene fraction, at the cost of being flammable. Supercritical CO2 extraction avoids that trade-off industrially, using pressurised CO2 as the solvent and leaving no residue, but needs equipment far beyond anything done at home.

"에탄올 추출법만 해도 사실 그 간이수공업 정도에서 구현을 할 수 있기 때문에 이제 소규모 디스펜서리나 농장에서 많이 활용을 하고 있고요 [...] 이제 합법적인 국가들에서 그렇게 하고 있고요." His own framing places ethanol at the small-scale, legal-jurisdiction end of this category, explicitly not Korea. On CO2: once close to a worldwide default, he says it's since been losing ground to hydrocarbon (butane) extraction, which pulls a fuller cannabinoid and terpene spectrum — a trend he dates to around 2019–2020, alongside Canadian and US legalisation driving demand for larger-scale production.

That last point is worth stating plainly rather than skipping past: home hydrocarbon extraction — running butane through plant material in an enclosed space — is a well-documented cause of fires and explosions, and is illegal in most jurisdictions outside a licensed facility for exactly that reason. Naming that this method exists is not the same as describing how to do it, and this lesson does neither.

"릭 심슨 오일 [...] 이분이 2003년도에 본인의 피부에 기저세포암을 진단을 받았고 당시에 이분께서 이제 논문이나 이런 자료를 찾아보시다가 THC가 이제 암세포를 죽인다는 효과가 있다는 논문을 보고 이제 직접 만들어서 사용을 한 거죠." A Canadian who, after a 2003 basal-cell-carcinoma diagnosis, produced his own full-extract cannabis oil — solvent-extracted (ethanol or isopropyl alcohol), retaining the plant's full range of cannabinoids rather than an isolate, high-THC ("약 60에서 70% 이상") — and self-reported a regimen of 60g over 90 days, doses ramped up, held, then tapered down.

That figure is Rick Simpson's own account of what he did, not a dose this course recommends or a claim this platform has verified. Dr. Kwon's own framing of it, matching his description of the wider full-extract category: an educational example of cannabis positioned as medicine, not guidance for anyone to follow.

Presented as a historical example only. This site does not verify or endorse the outcome Simpson reported, and offers no dosing guidance of its own — see the disclaimer on every service page.

Three terms do most of the work. Isolate is CBD alone, with every other plant compound removed — the cleanest claim to test, but, per the entourage hypothesis already covered, possibly the least representative of how whole-plant preparations act. Broad-spectrum keeps the other cannabinoids and terpenes but has THC specifically removed or reduced near zero. Full-spectrum keeps everything the extraction pulled out, including trace THC. Which category someone reaches for is usually decided by one practical constraint — a drug test, a legal THC limit — rather than a pharmacological one.

"사실 저가 CBD 오일 같은 경우는 아이솔레이트를 보통 많이 씁니다 [...] 아이솔레이트를 사용을 하게 되면 비율을 정확하게 맞출 수 있기 때문에 대량 생산을 하는 입장에서는 조금 더 유리한 것 같습니다." His own account of why: isolate gives a manufacturer an exact, reproducible ratio, which full-spectrum's naturally variable content does not — a production reason, not a claim that isolate works better.

A strain's 'profile' is usually reported as its cannabinoid ratio (THC:CBD, chiefly) plus its dominant terpenes — myrcene, limonene, pinene, caryophyllene and the rest, aromatic compounds found across the plant kingdom, not unique to cannabis. Terpenes are proposed to modulate the plant's overall effect, the mechanism the entourage hypothesis names, and at least one — caryophyllene — binds CB2 directly rather than merely accompanying THC and CBD.

Strain names themselves, 'indica', 'sativa', a proprietary name, are marketing categories, not verified chemotypes: two products sold under the same strain name can differ meaningfully in actual lab-tested content. A certificate of analysis, not a name, is what shows what is actually in a product.

His own deeper terpene teaching is a separate instructor's lecture in this course, not his — see e7's own comment on the same point.

A named list, not a generic gesture at 'other plants': "일단 황칠나무에 이제 CBD가 들어가 있고요. 그 미식재료로 유명한 송로버섯에는 아난다마이드라는 카나비노이드가 들어있습니다 [...] 그리고 에키나시아, 파라크레스, 헬리크리섬 뭐 이런 식물들에도 카나비노이드들이 들어있다라고 하고요." Hwangchil tree (황칠나무, Dendropanax morbifera) carries CBD; truffle carries anandamide; echinacea, para cress (파라크레스) and helichrysum are named as carrying cannabinoids too.

"차에는 카테킨이 들어있는데 이 카테킨도 카나비노이드 리셉터에 작용을 하는 카나비노이드다. 그리고 이제 베타카리오필렌이라고 하는 카나비노이드가 요새 또 많이 연구가 되고 있더라고요 [...] 대마 말고도 다른 여러 식물에 이제 포함이 돼 있고요." Tea's catechin acts on cannabinoid receptors too; beta-caryophyllene — the same terpene named above as binding CB2 directly — turns up across many plants beyond cannabis and is under active research.

One correction he volunteers himself: "한때 코파이바라는 그 식물이 좀 유행을 했어요 [...] 당시에 이제 사람들이 CBD가 카나비노이드의 약자라고 생각을 했던 모양인지 그 코파이바 오일에 CBD가 들어있다 이러면서 한때 좀 각광을 받았던 적이 있었는데, 사실은 베타카리오필렌이 들어있었던 겁니다." Copaiba essential oil had a vogue on the mistaken belief it contained CBD — people appear to have taken 'CBD' as shorthand for 'cannabinoid' generally — when what it actually carries is beta-caryophyllene. He also names basil (바질) and other herbs as carrying cannabinoids.

His own lecture draws a distinction the earlier draft here collapsed into one: "카나비노이드를 합성하는 방식이 [...] 생물학적인 방식이고 화학적인 방식이 있는데, 생물학적인 방식은 이제 이스트를 이용해서 [...] 효모를 이용해서 합성을 하게 되고요." Biosynthesis (yeast-fermentation) production of real cannabinoid molecules is one method — he names a handful of companies worldwide with this technology, one of which now operates in Korea. Separately, chemical synthesis can either reproduce a cannabinoid the plant already makes ("이미 식물에 존재하는 카나비노이드를 화학적으로 재현을 한 것" — his examples: Marinol and Cesamet, FDA-approved medications built this way) or design something new.

That third category — never in any plant, but built to act on the same receptor — is what he names by researcher or lab: "AM 같은 경우는 알렉산드로스 마클리아니스라는 분이 개발을 했다고 하고, JWH, 존 W호프만 선생님이 개발한 JWH 같은 경우는 굉장히 수많은 물질이 있는데요 [...] JWH133 같은 경우는 최근에 치매 치료제로 연구 개발을 하고 있고." AM (Alexandros Makriyannis), JWH (John W. Huffman — a large family of compounds, one of which, JWH-133, is in current dementia-treatment research), HU (Hebrew University) and CP (Pfizer) name the labs or developers behind each series, not a single drug.

He is direct about where this turns dangerous: certain JWH-series compounds circulate as 'Spice' or herbal incense on the illicit market — "신종 마약류로 분류가 될 거고요 [...] 어쨌든 좀 좋지는 않은 물질로 제가 알고 있고" — sold in Korea as a designated new psychoactive substance, and by his own account not something he regards well. Pharmacologically these compounds are frequently full CB1 agonists, considerably more potent and less predictable than THC's partial agonism, with no natural ceiling on the effect, and are often reformulated to stay ahead of drug scheduling — so a given batch's exact chemistry is often unknown even to the seller. This is not a stronger version of the same drug; it is a different pharmacological category that happens to target the same receptor.

References

1. Gertsch, J. et al. (2008). Beta-caryophyllene is a dietary cannabinoid. PNAS, 105(26), 9099–9104.●Caryophyllene binding CB2 directly, the exception to terpenes as mere accompaniment.
2. Woelkart, K. et al. (2008). CB receptor ligands from plants. Current Topics in Medicinal Chemistry.Plant-derived CB-receptor ligands outside cannabis.
3. Pacioni, G. et al. (2015). Truffles contain endocannabinoid metabolic enzymes and anandamide. Phytochemistry.Truffle-derived anandamide and its metabolic enzymes.
4. Trecki, J., Gerona, R. R. & Schwartz, M. D. (2015). Synthetic Cannabinoid-Related Illnesses and Deaths. New England Journal of Medicine, 373(2), 103–107.●Synthetic-cannabinoid illness and death reports.

Inhalation — smoking, vaporizing — gives the fastest onset, cannabinoids crossing from lung to bloodstream in seconds to minutes, and the shortest duration, since blood levels peak and fall quickly. "빠르게 작용을 하죠. 3분에서 10분 뒤면 피크를 치니까." Oral ingestion is the opposite: absorption is slow and unpredictable, but because it passes through the liver first, more of it converts to 11-OH-THC — the stronger, longer-lasting metabolite the earlier lesson on plant chemistry covers — which is why edibles are reported as more intense and much longer-lasting per equivalent dose.

"구강으로 투여를 했을 때는 용량 조절이 조금 용이한 거로 되어 있고요 [...] 제품화가 되어있는 걸 보면 THC가 몇 밀리그램, CBD가 몇 밀리그램 이렇게 딱 나와있는 것들이 있습니다." — commercial edibles with a labelled THC/CBD dose are easier to titrate; a homemade brownie, pasta or salad made with cannabis is not, since the dose isn't measured out the same way.

Two routes his own lecture adds that the earlier draft here didn't carry. Rectal and vaginal: "고대 이집트 파피루스의 치질로 인한 통증을 줄이기 위해서 대마를 좌약으로 만들어서 사용을 했다라는 기록이 있습니다 [...] 여성분들 같은 경우는 생리통이나 이런 부분들을 치료를 하기 위해서 생식기에 사용을 하기도 합니다." — an ancient Egyptian papyrus records a cannabis suppository for haemorrhoid pain, and modern use for menstrual pain follows the same route; bypassing first-pass liver metabolism, he notes this route shows higher absorption than swallowing. Transdermal: "이런 제품들이 개발되기 시작했던 것 같은데 [...] THC, CBD, CBN이 각각 3대 2대 1로 포함되어 있는 제품이고요. 피부에 붙이는 패치입니다 [...] 통증 조절용으로 많이 나오는 것 같고요 [...] 48시간짜리도 있고 24시간짜리도 있고." He dates patches to around 2011 and gives a 3:2:1 THC:CBD:CBN patch as his example, used mainly for pain control, with dose and delivery duration (24h/48h variants) both adjustable — unlike an ordinary topical lotion, which he treats as local-effect only.

THC is highly lipophilic and distributes into fat, redistributing there over hours to days — the mechanistic reason THC and its metabolites remain detectable in regular users for weeks after last use, long after any subjective effect has ended: it is being slowly released back out of fat stores rather than lingering in blood. It also binds plasma proteins heavily, largely albumin and lipoproteins, which limits how much circulates freely at any moment.

"90%는 혈장, 10%는 적혈구에 분포를 해서 혈액을 타고 큰 장기들, 뇌라든지 폐라든지 간 같은 혈류량이 큰 장기로 이동을 하게 됩니다. 그리고 활용이 되지 않거나 [...] 완전히 대사가 되지 않은 카나비노이드들은 지방조직에 분포하고 저장이 됩니다." His own figures: 90% plasma-bound, 10% carried on red blood cells, travelling first to the highest-blood-flow organs — brain, lungs, liver — before whatever isn't used or fully metabolised settles into fat.

"구강 섭취를 하는 경우에는 장에서부터 대사가 일어나고요. 호흡기로 섭취를 하는 경우에는 1차적으로 호흡기의 혈관을 통해서 흡수가 되고 한 바퀴 돌면서 간으로 들어갑니다. 간에서는 사이토크롬 P450 중합체 효소에 의해서 수산화가 일어나고 산화가 되면서 대사가 되는데요, 약 100여 가지의 대사산물이 확인이 됩니다." Metabolism begins in the gut for oral doses, or after one circulation pass for inhaled doses — either way the liver's cytochrome P450 enzymes do most of the work, hydroxylating and oxidising the molecule through roughly 100 identified metabolites.

He traces both main cannabinoids through that chain specifically. CBD: "CBD가 먼저 수산화가 되고 그 다음에는 카복시화가 되고 마지막에는 글루쿠론화가 되면서 글루쿠로나이드가 되면서 소변으로 배출이 되는." THC: "1차적으로는 수산화가 되면서 11-OH-THC로 바뀌게 되고, 이게 다시 카복시화가 되면서 11-COOH-THC가 되고, 마지막으로 글루쿠로나이드로 변환이 되면서 물에 녹아서 소변으로 배출이 됩니다." — hydroxylation, then carboxylation, then glucuronidation into a water-soluble form the kidneys can actually clear, for both molecules, matching the 11-OH-THC/THC-COOH chain the plant-chemistry lesson already names.

"보통 이 과정들이 5일 안에 일어나고요. 섭취를 한 카나비노이드의 80 내지 90%는 배출이 됩니다 [...] 만성적으로 혹은 많이 사용을 하는 사람들은 다 배출이 안되고 지방에 축적이 되게 되거든요. 길게는 두 달까지도 계속 배출이 일어날 수 있습니다." He gives roughly 5 days and 80–90% clearance as the ordinary case, but names chronic, heavy use specifically as the exception that extends detection out to two months, via the same fat-storage mechanism above.

On the split between routes out: "대부분의 대사산물들은 대변으로 나오게 되고 오직 20%만이 소변으로 배출됩니다." His own figure is roughly 80% faecal, 20% urinary — noticeably more faecal-weighted than the 'roughly two-thirds/a third' this lesson drew from general pharmacokinetic literature before this transcript arrived; his figure now leads. He also distinguishes which metabolite goes which way: the less-processed 11-OH-THC exits mainly in faeces, while the fully glucuronidated, more water-soluble metabolites are what actually reach urine — which is also why, in his account, the liver carries most of the real metabolic burden of cannabinoid use, for better (some anti-inflammatory liver effects he mentions) and worse (added hepatic load) at once.

Cannabis law varies sharply by country and changes often — confirmed directly rather than assumed: the same recording this lecture is drawn from is now years old, and its legal-status content would already be out of date if repeated here as fact. A course that states the law wrongly is worse than one that says 'check where you stand', which is this course's own rule from the start.

His own slide makes the same choice for the same reason: rather than asserting a jurisdiction-by-jurisdiction summary, it points to Wikipedia's continuously updated Legality of cannabis page. That page is not a source this platform is deferring to for lack of a better one — it is the honest answer to a question whose true answer changes faster than a course can be re-recorded.

References

1. Wikipedia contributors (2022). Legality of cannabis. Wikipedia, The Free Encyclopedia.SourceHis own lecture's source for this section — a living page, cited so a reader always sees current status rather than a frozen one.

Severe childhood epilepsies. Pharmaceutical-grade cannabidiol reduced convulsive seizure frequency in Dravet syndrome and Lennox-Gastaut syndrome in randomised, placebo-controlled trials, and is licensed for them. This is the strongest evidence in the field, and it is worth noting what made it strong: a purified single molecule, a defined dose, a hard endpoint, and a placebo arm.

Chemotherapy-induced nausea and vomiting. Synthetic cannabinoid antiemetics have decades of use for this indication.

Spasticity in multiple sclerosis. A THC:CBD oromucosal spray is licensed in a number of countries, with modest effect sizes that are real and not large.

Chronic non-cancer pain is the largest use in practice and the most contested in evidence. The 2015 JAMA systematic review found only moderate-quality evidence for chronic pain and spasticity, and low-quality evidence for most other indications; the 2017 US National Academies report reached a similar shape. Neither says cannabinoids do not help pain. Both say the evidence is thinner than the enthusiasm.

Also here: anxiety, sleep, post-traumatic stress, inflammatory bowel disease, appetite in wasting syndromes. Signals exist. Trials are frequently small, short, unblinded — cannabinoids are notoriously hard to blind — or industry-linked. Emerging is the honest label, and it is not a dismissal.

A physician who lists only benefits has stopped practising medicine. Cannabis use disorder is real and more common with early onset, high potency and frequent use. Psychosis risk is consistently associated with heavy use of high-potency products, with adolescent exposure carrying the strongest association — causality remains debated, the association does not. Cognitive effects on attention and memory are acute and reliable; adolescent trajectories are the live research question. Cannabinoid hyperemesis syndrome — cyclical vomiting in long-term heavy users, relieved by hot showers and by stopping — is under-recognised and frequently misdiagnosed for years. Interactions: CBD inhibits cytochrome P450 enzymes and will raise levels of some other drugs, which is exactly the kind of quiet, serious problem that supplement-shaped thinking misses.

Four questions handle most of it. Was it a defined molecule at a defined dose, or a plant product of unknown composition? Was there a placebo arm, and could anyone plausibly be blinded? Was the endpoint hard, or self-reported over two weeks? And who funded it?

Apply those and the field sorts itself quickly: a small evidence base of genuine strength, a large one of legitimate uncertainty, and a marketing layer far larger than both.

References

1. Devinsky, O. et al. (2017). Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. New England Journal of Medicine, 376, 2011–2020.●The strongest trial evidence in the field.
2. Whiting, P. F. et al. (2015). Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA, 313(24), 2456–2473.●Moderate-quality evidence for pain and spasticity; low for most else.
3. National Academies of Sciences, Engineering, and Medicine (2017). The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.●The most comprehensive evidence audit available; used here for both benefits and harms.
4. Allen, J. H. et al. (2004). Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut, 53(11), 1566–1570.●The original description of a syndrome still routinely missed.
5. Moore, T. H. M. et al. (2007). Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. The Lancet, 370(9584), 319–328.●The association that any honest course must state.

His slide's THC entry names the same partial-agonist mechanism e4 covers, plus a specific effect list: pain relief, relaxation, improved insomnia, appetite increase, muscle spasm relief, and an antidepressant effect. Its CBD entry frames CBD's action at CB1/CB2 as antagonist rather than e4's negative-allosteric-modulator framing — the two descriptions point at the same low-affinity, non-activating relationship to the receptor, worded differently — and adds a specific effect list of its own: relief of chronic pain from muscle stiffness, spasm and inflammation; symptom relief in multiple sclerosis, fibromyalgia and epilepsy; effective improvement in anxiety-related disorders; and, injected alongside THC, suppressed cancer-cell growth in breast cancer and brain tumours specifically.

That last claim, and several of the others, are clinical outcomes rather than receptor pharmacology, and this lesson is not the place they get evaluated — see e5's clinical ledger and the tiers it already applies to CBD's strongest evidence (Dravet and Lennox-Gastaut) versus its weaker ones. Named here because it's what his slide says, not asserted as this platform's own clinical claim.

This section names his slide's content; it does not re-argue e4's tiers. Where the two frame the same mechanism differently — antagonist versus negative allosteric modulator — that is a difference in how plainly to state a low-affinity interaction, not a factual disagreement.

His slide lists cannabichromene as non-psychoactive, with an antidepressant effect, an ability to enhance THC's own pain relief, a sedative effect that promotes relaxation, promotion of nerve regeneration, antibacterial and antifungal action, and — matching what published pharmacology already says about CBC's weak affinity for CB1/CB2 — action at non-cannabinoid receptors specifically.

Cannabigerolic acid (CBGA) is the precursor the biosynthesis lesson traced into THCA, CBDA and CBCA — but not all of it converts, and what remains becomes CBG. His slide names it non-psychoactive, with pain relief and anti-inflammatory effect, a pressure-lowering effect relevant to glaucoma specifically, an antibiotic role, a neuroprotective role, and — the one receptor mechanism his slide states plainly — CB1 antagonist.

His slide names tetrahydrocannabivarin for appetite suppression and metabolic regulation, memory enhancement and calm, antibacterial and antiviral action, and immune-system support — and gives it a receptor profile split by target: CB1 antagonist, CB2 partial agonist. Published pharmacology adds one further wrinkle his slide doesn't state: at higher doses THCV can act as a partial agonist at CB1 too, the opposite direction from its low-dose antagonism — worth knowing, but that dose-dependent switch is this lesson's addition, not his slide's.

His slide names bone-growth promotion, an analgesic and antispasmodic effect, an anxiolytic effect, and sedation alongside anxiety improvement, with a receptor profile of CB1 and CB2 agonist — not antagonist, unlike CBG and THCV above. What it doesn't restate is the point the biosynthesis and degradation lesson already made: cannabinol isn't synthesised directly by the plant in any quantity, but forms as THC oxidises with age, heat and light, and binds CB1 far more weakly than THC does — the pharmacological reason aged cannabis is widely reported as more sedating and less intoxicating. The popular claim that CBN specifically drives sleep still has more anecdote behind it than trial evidence.

References

1. Izzo, A. A., Borrelli, F., Capasso, R., Di Marzo, V. & Mechoulam, R. (2009). Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in Pharmacological Sciences.◗The likely source of a pie-chart figure his slide reproduces, grouping effects by CBD/CBDV/THCA/CBC/CBG/THCV — matched by the figure's own journal watermark and cannabinoid lineup, not independently confirmed.

Everything below is transcribed from slides in his own lecture, reproducing published mechanism diagrams and a list of conditions the cannabinoid literature has studied. It is corpus in the same sense s7-s10 are: his own teaching material, edited for the screen, not invented. It is not this platform's clinical claim about any named condition, and nothing here is instruction to use a cannabinoid for anything. The disclaimer on every page of this site — nothing here diagnoses or treats a condition — applies to this lesson at least as much as any other, and more literally than most.

His slide reproduces a published diagram (matching Fernández-Ruiz et al.'s 2015 review, already cited in the reference lesson) centred on 'cannabinoid-based therapies', branching out to six conditions with a proposed mechanism attached to each: Huntington's disease, via CB1/CB2 receptor activation and PPAR/Nrf-2/NF-κB signalling. Alzheimer's disease, via FAAH and MAGL inhibition, CB1/CB2 activation, and the same PPAR/Nrf-2/NF-κB pathway. Stroke and brain trauma, via CBD acting on 5-HT1A receptors, CB1/CB2 activation, and inhibition of endocannabinoid hydrolysis. Parkinson's disease, via CB2 activation, CB1 blockade, and PPAR/Nrf-2/NF-κB signalling. Amyotrophic lateral sclerosis, via FAAH/MAGL inhibition, CB1/CB2 activation, and the same pathway again. Neonatal hypoxia-ischemia, via CBD acting on CB2, 5-HT1A and A2A receptors together.

Six different conditions converging on two or three repeated mechanisms — receptor activation, enzyme inhibition, one recurring signalling pathway — is itself worth noticing: this is a diagram of proposed shared mechanism, not six independent bodies of clinical proof. Fernández-Ruiz et al.'s own title says as much: 'from preclinical models to clinical applications' is a distance, not a completed trip.

A second diagram, on cannabinoids' anticancer action, likely drawn from the same cancer review already cited in the reference lesson (Mangal et al., 2021). It shows THC, CBD, CBG and the endocannabinoids AEA and 2-AG acting on a wider receptor set than this course has named together before: CB1/CB2, TRPV1/TRPV2/TRPM8, and GPR55. Downstream, the diagram traces two convergent routes — de novo ceramide synthesis leading to ER stress and reactive oxygen species, and RhoA/ROCK signalling affecting the actin cytoskeleton — both ultimately reaching the cell's fate machinery: cell-cycle arrest (via p21/p27, blocking proliferation), autophagy, and apoptosis.

This is a mechanism diagram, not a trial result: it shows what cannabinoids are proposed to do to a cancer cell in laboratory models, not what a course of treatment does in a patient. Held at the same tier e5 already gives cancer research generally.

His slide's COVID-19 section — matching the paradigm paper already cited in the reference lesson (Palan et al., 2021) — lists ten proposed mechanisms rather than a diagram: strengthening the endocannabinoid system and regulating ACE2; suppressing inflammatory cytokines; preventing cellular oxidative stress; inhibiting TLR4 (the intracellular signalling pathway responsible for NF-κB activation and inflammatory cytokine production in innate immunity); inhibiting the adenosine A2A receptor, which regulates glutamate and dopamine release; preventing hypoxic damage to brain, lung and heart tissue; preventing bacterial resistance as a complement to antibiotic treatment; stabilising membrane permeability in the lungs; regulating immune-cell migration to the lungs and inhibiting exosome release of virions from infected cells; and improving immune responsiveness through intracellular zinc regulation, by a mechanism his slide states is the same as chloroquine's.

That last point resolves something the reference lesson could not: it cites a 2011 paper on cannabidiol and zinc-homeostasis gene expression in microglial cells, grouped with the COVID-19 references despite predating the pandemic by nearly a decade. His slide's zinc bullet is exactly why — the paper is cited for the zinc mechanism, not for COVID-19 itself, and belongs on this list on that basis rather than by date.

Proposed mechanisms are not a treatment claim. None of this is guidance to use a cannabinoid for COVID-19, and this platform makes none.

The clip closes with a list of conditions grouped by organ system, each paired with a proposed action. Ophthalmological: lowers intraocular pressure — glaucoma. Respiratory: bronchodilation — asthma, COPD. Digestive: antiemetic and improved digestive function — irritable bowel syndrome, Crohn's disease, and reduced side effects with improved efficacy in hepatitis C treatment. Endocrine: metabolic regulation and improved glucose utilisation — obesity, diabetes, metabolic syndrome. Neurological: anticonvulsant, pain relief, anti-inflammatory — epilepsy, Dravet syndrome, Parkinson's disease, multiple sclerosis, cerebral palsy, polio, Alzheimer's/dementia, cerebral haemorrhage, concussion. Psychiatric: antidepressant, anxiolytic, sleep-rhythm restoration — anxiety disorder, depression, insomnia, panic disorder, PTSD, substance addiction. Cancer: suppressing cancer-cell growth and metastasis, pain relief — breast cancer, brain tumour, colon cancer, and mitigating chemotherapy side effects. Joints: pain relief, anti-inflammatory, tissue-regeneration promotion — degenerative arthritis, gout, fracture. Autoimmune disease: immune regulation, anti-inflammatory — psoriasis, lupus, fibromyalgia, coeliac disease, rheumatoid arthritis. Skin: anti-inflammatory, regeneration promotion — wound healing, dermatitis.

His slide continues into a cardiovascular category and a further 'other' category naming menstrual pain among other conditions, but the recording cuts off mid-list at both — transcribed only as far as it is legible, not completed from guesswork.

This is his own slide's survey of what the cannabinoid literature has studied, condition by condition — a scope, not a scorecard. It says nothing about dose, quality of evidence per condition, or whether any individual should act on it, and none of that is supplied here. Read it the way e5 teaches: as raw material for the four questions — defined molecule or plant product, placebo-controlled or not, hard endpoint or self-report, and who funded it — not as a menu.

References

1. Fernández-Ruiz, J. et al. (2015). Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications. Neurotherapeutics.◗The likely source of the neurodegenerative-disease diagram his slide reproduces.
2. Mangal, N. et al. (2021). Cannabinoids in the landscape of cancer. Journal of Cancer Research and Clinical Oncology.◗The likely source of the cancer-mechanism diagram his slide reproduces.
3. Afrin, F., Chi, M., Eamens, A. L., Duchatel, R. J., Douglas, A. M., Schneider, J., Gedye, C., Woldu, A. S. & Dun, M. D. (2020). Can Hemp Help? Low-THC Cannabis and Non-THC Cannabinoids for the Treatment of Cancer. Cancers, 12(4), 1033.◗An independent review covering the same receptor set his diagram names — CB1/CB2, TRPV1/2, and non-THC cannabinoids acting through de-orphaned GPCRs — with a cell-line and clinical-trial table. Not the source of his slide; added because it corroborates the mechanism from a second, separately-checkable review rather than his diagram alone.
4. Ramer, R., Wendt, F., Wittig, F., Schäfer, M., Boeckmann, L., Emmert, S. & Hinz, B. (2022). Impact of Cannabinoid Compounds on Skin Cancer. Cancers, 14(7), 1769.◗A skin-cancer-specific review, naming the same CB1/CB2/anti-proliferative mechanism at the one organ this course's own body map (lib/ecs/) also carries cannabinoid receptor data for — added for that overlap, not because his slide names skin cancer specifically.
5. Palan, N. et al. (2021). The Immunopathology of COVID-19 and the Cannabis Paradigm. Frontiers in Immunology.◗The COVID-19 paradigm paper his slide's ten-point mechanism list draws on.
6. Juknat, A. et al. (2011). Cannabidiol affects the expression of genes involved in zinc homeostasis in BV-2 microglial cells. Neurochemistry International.The zinc-homeostasis mechanism behind this slide's chloroquine-comparison bullet — resolves why the reference lesson found it grouped with COVID-19 papers despite predating them.

For decades the euphoria after sustained exercise was attributed to endorphins. The problem is size: endorphins are large peptides and do not readily cross the blood–brain barrier, so the story never quite worked. Endocannabinoids are small lipids that cross easily, and they rise measurably with sustained moderate exercise.

In 2015 Fuss and colleagues closed the loop in mice: block cannabinoid receptors and the running-induced anxiolysis and analgesia disappear. Blocking opioid receptors did not abolish it. The runner's high, at least in that model, depends on this system.

Sustained aerobic exercise raises circulating endocannabinoids most reliably. Dietary fat composition supplies the precursors, since these are lipids built from arachidonic acid. Sleep, stress and social contact all interact with the system in directions that are documented but not simple.

I mark this whole area emerging on purpose. That exercise raises endocannabinoids is established; that you can meaningfully train your endocannabinoid tone as a health strategy, with outcomes that matter, is a reasonable hypothesis wearing a lot of supplement marketing. The distance between those two sentences is the discipline this course is teaching.

It would be easy, and wrong, to claim that breath practice tunes your endocannabinoid system. I am not claiming it. What I will say is narrower and better supported: the practices taught elsewhere on this platform act on autonomic state through pathways that are separately measured — baroreflex coupling, vagal tone, heart-rate variability — and that autonomic state and endocannabinoid signalling are neighbours in the same regulatory neighbourhood.

That is an honest adjacency, not a mechanism. If someone eventually measures 調息 practice against endocannabinoid markers, we will know something we currently do not. Until then this lesson sits at observation, and says so.

항상성 — 몸이 스스로 균형을 유지하는 능력.

The endocannabinoid system is the clearest example on this platform of something the body does quietly, constantly, and without instruction — a governor holding a dozen systems inside their range. The traditions described a regulating principle long before anyone could name a receptor, and they were describing something. What has changed is that part of it is now measurable, and where it is measurable we should say so precisely, and where it is not we should say that too.

That is the whole method, arriving from the biochemical end instead of the contemplative one.

References

1. Fuss, J. et al. (2015). A runner's high depends on cannabinoid receptors in mice. Proceedings of the National Academy of Sciences, 112(42), 13105–13108.●The study that reassigned the runner's high from opioids to this system.
2. Raichlen, D. A. et al. (2012). Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals. Journal of Experimental Biology, 215(8), 1331–1336.●Exercise-induced endocannabinoid rise in humans.

On trichomes as the site of production, and on the biosynthesis pathway covered in the earlier lesson on how the plant builds these molecules.

A narrative review of processing and extraction methods, a paper optimising supercritical CO2 extraction specifically, and an industry explainer on hydrocarbon extraction — named in the earlier lesson on how cannabis is used, without the how-to.

How cannabinoid metabolites interact with the liver's CYP450 enzyme family — relevant to drug interactions, since CYP450 is also how many prescription medications are cleared.

Plant-derived CB-receptor ligands are not unique to cannabis: truffles contain endocannabinoid metabolic enzymes and anandamide itself, and a Korean native plant extract (Dendropanax morbiferus) has been studied for effects on oligodendrocyte development — a reminder that this receptor system predates, and extends well past, the one plant most associated with it.

The paper that found it — Devane, Mechoulam and colleagues' 1992 isolation of the first identified endocannabinoid — alongside a 25-years-later review of its metabolism, a study on its role in stress, emotionality and inflammation, and a New York Times opinion piece his slide cites by URL alone.

On CB1 receptor distribution in the brain and its relevance to drug policy; on stress and the brain's own endocannabinoid tone; and on the system's documented role in pain, by way of the brain-gut axis.

Ethan Russo's clinical endocannabinoid deficiency hypothesis, cannabinoids in the landscape of cancer research, their role in neurodegenerative disease and stroke/brain trauma, two papers connected to COVID-19, and a review of cannabis in gastrointestinal and hepatic disease.

The Cannabis Education Guild (CEG) — an international NGO doing cannabis-related education and consulting, cannabiseducationguild.com, collaborating with the Korean Cannabinoid Association since 2020. Its team, as shown on his slide, includes Dr. Marcus Kwon (his own working name), Dr. Carolina Nocetti, Dr. Ira Price, and Neelan Mohan.

The International College of Cannabinoid Medicine (ICCM) — an online education platform, per his slide, gathering authorities in cannabinoid medicine, iccm.co, under an agreement with the Korean Cannabinoid Association since 2022. His slide also names a 10% discount code (A-KCA-21) tied to that agreement.

Not only an institutional link: he holds seven ICCM CPD certificates himself, completed within twenty days in February 2022 — Overview of Medicinal Cannabis: Foundations, The Endocannabinoid System in Health and Disease, Cannabis Pharmacokinetics, Safety of Medicinal Cannabis, CBD Prescribing Considerations, and Medical Cannabis in Treatment of Chronic Pain, Parts 1 and 2 — the same month the KCA agreement is dated to, and in an order that reads as a full curriculum rather than scattered modules.

References

1. Tanney, C. A. S. et al. (2021). Cannabis Glandular Trichomes: A Metabolite Factory. Frontiers in Plant Science.Cannabis glandular trichomes as the site of cannabinoid production.
2. Tahir, M. N. et al. (2021). The biosynthesis of the cannabinoids. Journal of Cannabis Research.The biosynthesis pathway itself.
3. Lazarjani, M. P. et al. (2021). Processing and extraction methods of medicinal cannabis: a narrative review. Journal of Cannabis Research.Narrative review of processing and extraction methods.
4. Rochfort, S. et al. (2020). Utilisation of Design of Experiments Approach to Optimise Supercritical Fluid Extraction of Medicinal Cannabis. Scientific Reports.Optimising supercritical CO2 extraction specifically.
5. Precision Extraction (2019). What Is Hydrocarbon Extraction? precisionextraction.com.SourceIndustry explainer on hydrocarbon extraction, cited as such — not peer-reviewed evidence.
6. Nasrin, S. et al. (2022). Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions. Drug Metabolism and Disposition.Cannabinoid metabolites and hepatic CYP450 drug interactions.
7. Zendulka, O. et al. (2016). Cannabinoids and Cytochrome P450 Interactions. Current Drug Metabolism.Cannabinoids and cytochrome P450 interactions generally.
8. Woelkart, K. et al. (2008). CB receptor ligands from plants. Current Topics in Medicinal Chemistry.CB receptor ligands found in plants other than cannabis.
9. Pacioni, G. et al. (2015). Truffles contain endocannabinoid metabolic enzymes and anandamide. Phytochemistry.Truffles containing endocannabinoid metabolic enzymes and anandamide itself.
10. Kim, J.-Y. et al. (2019). Dendropanax morbiferus leaf extract facilitates oligodendrocyte development. Royal Society Open Science.A Korean native plant extract studied for effects on oligodendrocyte development.
11. Devane, W. A. et al. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258(5090), 1946–1949.●The original isolation of anandamide — already cited in an earlier lesson on the system's discovery.
12. Maccarrone, M. (2017). Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years. Frontiers in Molecular Neuroscience.A 25-years-later review of anandamide's metabolism.
13. Crowe, M. S. et al. (2014). The endocannabinoid system modulates stress, emotionality, and inflammation. Brain, Behavior, and Immunity.The endocannabinoid system's role in stress, emotionality and inflammation.
14. The New York Times, Sunday Review, opinion piece (2015-03-08) on genetics and altruism — cited by URL slug ('good-gene') only; title and author are not confirmable from the source slide.Cited by his slide via URL only; title and author not confirmed from the source.
15. Baler, R. D. (2017). Building smart cannabis policy from the… International Journal of Drug Policy.CB1 receptor distribution in the brain, in the context of drug policy.
16. Sharkey, K. A. (2016). The Role of the Endocannabinoid System in the Brain-Gut Axis. Gastroenterology.Stress and the brain's own endocannabinoid tone, via the brain-gut axis.
17. Maldonado, R. (2015). The endocannabinoid system and neuropathic pain. Pain.The endocannabinoid system's documented role in neuropathic pain.
18. Russo, E. B. (2004). Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinology Letters.The clinical endocannabinoid deficiency hypothesis.
19. Mangal, N. et al. (2021). Cannabinoids in the landscape of cancer. Journal of Cancer Research and Clinical Oncology.Cannabinoids in cancer research.
20. Fernández-Ruiz, J. et al. (2015). Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications. Neurotherapeutics.Cannabinoids in neurodegenerative disorders and stroke/brain trauma.
21. Juknat, A. et al. (2011). Cannabidiol affects the expression of genes involved in zinc homeostasis in BV-2 microglial cells. Neurochemistry International.Grouped with the COVID-19 papers on his slide despite predating COVID-19 by nearly a decade — the reason resolves in the lesson on his indications survey: it's cited for the zinc-homeostasis mechanism, not the disease.
22. Palan, N. et al. (2021). The Immunopathology of COVID-19 and the Cannabis Paradigm. Frontiers in Immunology.The immunopathology of COVID-19 and the cannabis paradigm.
23. Gotfried, J. et al. (2020). Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease. Reviews and Perspectives: Reviews in Basic and Clinical Gastroenterology and Hepatology.Cannabis and its derivatives in gastrointestinal and hepatic disease.